This invention relates to compositions of basic drugs, zwitterionic drugs, or salts of either that have improved solubility, hence bioavailability, in the small intestine, to processes for testing such compositions, and to methods of using such compositions. In particular, it relates to compositions comprising a basic or a zwitterionic drug and a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP). The invention further relates to a method for increasing the bioavailability of a basic or a zwitterionic drug comprising co-administering the basic or zwitterionic drug with any one or more of the aforementioned polymers.
It is known in the pharmaceutical arts that low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. A drug which forms a zwitterion can also exhibit poor solubility, depending on its pKas and on the pH of its aqueous use environment.
Many basic drugs are quite bioavailable, although bioavailability can be dose-dependent. In the low pH environment of the stomach (pH 1-2, usually about 1.2), a basic drug may be soluble. When the drug solution passes into the higher pH environment of the small intestine where the pH is 5 to 7, usually about 6.5, the drug may be above its equilibrium solubility at that pH. However, if the dose is relatively low and if the drug has the capacity to temporarily supersaturate, the drug may maintain supersaturation in the small intestine for a time, thus permitting absorption of the dissolved drug across the intestinal wall. In general, the residence time in the small intestine of humans is around 4 hours. Thus, a drug which can maintain supersaturation at intestinal pH will, in general, be better absorbed than one which does not.
Zwitterionic drugs can be affected by the same considerations. That is, even though a drug forms ions in aqueous use environments having acid and/or basic pHs, and thereby exhibits good solubility in such use environments, the same drug may be poorly soluble in an aqueous use environment having a pH at which the drug assumes its neutral form and the neutral form intrinsically exhibits poor aqueous solubility at that pH.
Some basic and zwitterionic drugs exhibit xe2x80x9cdose/solubility-limited exposurexe2x80x9d. As the dose is increased, the systemic drug exposure increases until a limiting dose is achieved, above which dose the increase in systemic exposure with increasing dose is less than that observed at doses lower than this dose. Since basic and zwitterionic drugs are generally soluble at gastric pH, this effect may be due to precipitation of drug in the small intestine above the limiting dose.
Some basic drugs exhibit little or no capacity to be supersaturated at neutral pH; such drugs precipitate quickly in the small intestine even if reasonably soluble in the stomach, and are poorly bioavailable.
It is not generally possible to predict the propensity of a basic drug to supersaturate the small intestinal lumen.
Miyajima et al., U.S. Pat. No. 4,983,593 relates to the destruction of drug crystallinity by drying a solution of drug and polymer. Miyajima discloses, inter alia, formulating HPMCAS with a drug designated as NZ-105. The patent disclosed that there is formed xe2x80x9c. . . a composition having a remarkably enhanced bioavailability and easily prepared into tablets, capsules, granules, powders, and the like . . . xe2x80x9d The patent teaches that the formulations can be prepared by dissolving NZ-105 and HPMCAS in an organic solvent and removing the solvent by means of vacuum-drying, spray-drying, freeze-drying, or the like, or by coating a filler such as an inorganic salt (e.g., calcium hydrogen phosphate) or a sugar (e.g., lactose, sucrose, and so forth) and the like by means of a fluidized bed granulation method, a centrifugal coating method, or a pan coating method to produce granules.
Nakamichi et al., U.S. Pat. No. 5,456,923, disclose, inter alia, a process for producing solid dispersions by passing a mixture of a drug and a polymer carrier through a twin screw compounding extruder. A large list of polymers which can be used is disclosed.
Miyamoto, PCT/JP96/02246, discloses hydroxypropylmethylcellulose (HPMC), HPMCAS, and poly(vinyl acetate) (PVA) as part of an extensive list of amorphous stabilizers. Miyamoto discloses amorphous dispersions of drug plus amorphism inducing agent plus amorphism stabilizer, formed by heating, milling, or precipitation from a solvent.
U.S. Pat. No. 5,456,923 to Shogo et al. discloses an extrusion method for making solid dispersions. HPMCAS is included in a list of polymeric materials, including materials such as starch or gelatin, that can be used as matrix materials.
Takeichi et al., Chem. Pharm. Bull, 38 (9), 2547-2551 (1990) relates to the destruction of drug crystallinity by co-grinding with other agents. Takeichi attempted to use a solid dispersion of HPMCAS and uracil made by grinding in a ball mill to enhance rectal absorption, but concluded that uracil absorption was lower than for low molecular weight matrix materials such as sodium caprate. The use of HPMCAS was not recommended.
Baba et al., Chem. Pharm. Bull, 38 (9), 2542-2546 (1990) relates to the destruction of drug crystallinity by co-grinding with other agents. Baba made ground mixtures of uracil and HPMCAS along with 50 other matrix materials. Although some enhancement (about a factor of 2) in the dissolution of uracil was observed in the co-ground HPMCAS material relative to a simple mixture of crystalline drug and HPMCAS, the enhancement decreased as the polymer-to-drug ratio was increased. This led the researchers to conclude that HPMCAS adsorbed on the surface of the uracil thereby hindering the dissolution of uracil. Its use was not recommended.
T. Yamaguchi et al., Yakuzaigaku, 53 (4), 221-228 (1993) relates to the destruction of drug crystallinity by spray-drying drug and polymer to form: a dispersion. Yamaguchi prepared solid amorphous dispersions of 4xe2x80x3-O-(4-methoxyphenyl)acetyltylosin (MAT) in HPMCAS as well as carboxymethylethylcellulose (CMEC). Dissolution tests at pH 4.0 showed supersaturated concentrations of MAT 9-fold that of crystalline MAT with HPMCAS dispersions. This concentration was comparable to that obtained with the dissolution of amorphous drug alone. However, the presence of HPMCAS sustained the supersaturation longer than the amorphous drug alone. The authors report that even better results were obtained with the CMEC dispersions, however, causing the authors to conclude that CMEC is the preferred dispersion matrix.
In a first aspect, this invention provides a composition comprising
a) a basic drug, a drug which forms a zwitterion, or a salt of either, admixed with
b) a polymer selected from the group consisting of hydroxypropylmethyl-cellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);
wherein, in the absence of said polymer, said basic drug, zwitterionic drug or salt has a solubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second aqueous use environment having a pH in the range of 5.0 to 7.0;
and wherein, in said composition, said polymer is present in an amount such that, at any time during the first two hours following the time at which said composition has been introduced from said first use environment into said second use environment, the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment is increased to at least 1.5-fold, preferably 2-fold, more preferably 5-fold, the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer.
The term xe2x80x9cpolymerxe2x80x9d as used herein, including the claims, is used as a shorthand notation to refer to any one of hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP). The term shall also be understood to mean mixtures of any two or more of the aforementioned polymers.
A preferred subgroup of polymers for use in the invention is HPMCAS, CAT, and CAP. This group of polymers shall be understood to include mixtures of any two or of all three.
Most preferred for use in the invention is HPMCAS.
While not wishing to be bound by theory or mechanism, it is believed that, surprisingly, a simple physical mixture, including a wet or dry granulation, of a basic drug, a zwitterionic drug, or a salt of either, with one or more of the aforementioned polymers, can slow or retard the precipitation of the basic or zwitterionic drug when the pH of a use environment containing such a drug is raised from gastric pH to intestinal pH.
For the sake of convenience, reference hereinafter to a xe2x80x9cbasic drugxe2x80x9d shall be understood as also including zwitterionic drugs and salts of either entity.
A basic drug does not necessarily have to be sparingly soluble at near-neutral pH (pH 5-7) in order to benefit from this invention, although sparingly soluble basic drugs represent a preferred class for use with the invention. Even a basic drug that nonetheless exhibits appreciable solubility at near-neutral pH can benefit from the increased solubility/bioavailability made possible by this invention if the addition of a polymer further increases its solubility and/or bioavailability, since increasing bioavailability can reduce the size of the dose needed for therapeutic efficacy.
In a further aspect, this invention provides a method of administering a basic drug, a drug which forms a zwitterion, or a salt of either, comprising co-administering, to a patient in need of said drug:
a) said basic drug, zwitterionic drug, or salt of either, and
b) a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);
wherein, in the absence of said polymer, said basic drug, zwitterionic drug or salt of either has a solubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second aqueous use environment having a pH in the range of 5.0 to 7.0;
and wherein said polymer is co-administered in an amount such that, at any time during the first two hours following the time at which said basic drug, zwitterionic drug, or salt of either has been introduced from said first use environment into said second use environment, the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment is increased to at least 1.5-fold, preferably 2-fold, more preferably 5-fold, the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. The method generally improves the solubility of the drug in near-neutral or neutral use environments (pH 5.0-7.0), and also its bioavailability. The amount of polymer is generally such that the improvement in solubility and/or bioavailability lasts for at least fifteen minutes, preferably at least thirty minutes.
It should be noted that the aforementioned polymers do not have the capacity to appreciably solubilize basic or zwitterionic drugs at intestinal pH. As discussed above, and while not wishing to be bound by theory or mechanism, it is believed the polymer is acting to slow the rate of precipitation of such a drug when the drug is initially solubilized (e.g, in the stomach at a pH of 1.0 to 2.0), and then the pre-solubilized drug undergoes a pH increase up to intestinal pH (e.g, as by traveling from the stomach into the small intestine).
The basic drugs suitable for use in this invention can be crystalline or amorphous. Further, the invention has wide applicability and is not limited by or to any particular class of basic drugs. The only types of basic drugs for which the invention may not be as useful are those which, even though they may show a relatively reduced solubility at the pH of the small intestine, are still sufficiently potent to be efficacious because they have (a) an adequate intestinal solubility, (b) an adequate intestinal absorption rate, and (c) a sufficiently low dose, permitting absorption of the complete dose.
The term xe2x80x9cdrugxe2x80x9d in this specification and the appended claims is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially a human.
The term xe2x80x9csaltxe2x80x9d generally means pharmaceutically acceptable salts.
The term xe2x80x9cadmixed withxe2x80x9d refers to the fact that compositions of drug and polymer are simple physical mixtures of the type achieved by combining and physically stirring dry components together. Such physical mixtures include wet and dry granulated mixtures. As is known in the art, granulation is a process used to improve the handling and manufacturing properties of a formulation, for example by increasing particle size to improve flow. Granulation does not substantially change the physical form of the drug such as its crystalline or amorphous character. Granulation is not intended to create an amorphous drug/polymer dispersion.
Compositions comprising dispersions, particularly molecular dispersions, of drug and HPMCAS, as disclosed in the art discussed above, do not form a part of this invention. Thus, compositions made by dissolving a drug plus excipients in a solvent followed by drying from the solvent, or by co-grinding, or by extruding with heating or by other methods do not form a part of this invention.
The term xe2x80x9cconcentration of said basic dissolved drug, zwitterionic drug, or salt of eitherxe2x80x9d is typically taken as referring to that material that either passes a 0.45 xcexcm syringe filter or, alternatively, the material that remains in the supernatant following centrifugation of a sample. Filtration can be conducted using a 13 mm, 0.45 xcexcm polyvinylidine difluoride syringe filter sold by Scientific Resources under the trademark TITAN(copyright). Centrifugation can be typically carried out in a polypropylene microcentrifuge tube by centrifuging at 13,000 G for 60 seconds. It is recognized that this definition of xe2x80x9cdissolved drugxe2x80x9d encompasses not only monomeric solvated drug molecules but also a wide range of species that have submicron dimensions such as drug aggregates, aggregates of mixtures of polymer and drug, micelles, polymeric micelles, colloidal particles or nanocrystals, polymer/drug complexes, and other such drug-containing species that are present in the filtrate or supernatant in the: specified dissolution test.
A xe2x80x9csparingly-soluble basic drugxe2x80x9d as employed above applies to drugs which are essentially totally water-insoluble or poorly water-soluble at any pH in the range of pH 5.0 to pH 7.0. More specifically, the term applies to any beneficial therapeutic agent which has a dose (mg) to aqueous solubility (mg/ml) ratio greater than 100 ml, where the drug solubility is that of the form or mixture of forms present in the pH range of 5.0 to 7.0. This definition includes but is not limited to basic drugs that have essentially no aqueous solubility (less than 1.0 xcexcg/ml) since the invention can have benefit for such drugs.
A xe2x80x9cuse environmentxe2x80x9d as employed herein generally means the gastrointestinal tract if in vivo and aqueous test medium if in vitro. More specifically, xe2x80x9cuse environment meansxe2x80x9d (1) if the use environment is in vivo and has a pH in the range of 1.0 to 2.0, the stomach; (2) if the use environment is in vivo and has a pH in the range of 5.0 to 7.0, the small intestine; (3) if the use environment is in vitro and has a pH in either of the ranges just mentioned, aqueous test fluid which is initially at a pH of 1.0 to 2.0 and which is then adjusted to within the range 5.0 to 7.0, as further described below. A composition according to the invention can be tested in vivo or, more conveniently, tested in vitro as further disclosed and discussed below to ascertain whether it is within the scope of the invention.
Similarly, reference to a drug having a xe2x80x9csolubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second use environment having a pH in the range of 5.0 to 7.0xe2x80x9d means that the equilibrium solubility of the drug at any one or more particular points in the range of 1.0 to 2.0 is 3-fold the equilibrium solubility of the drug at any one or more points in the pH range 5.0 to 7.0. Further, the quoted language refers to a drug which is first dissolved in the first use environment (i.e., of pH 1.0 to 2.0) and then introduced into the second (i.e., pH 5.0 to 7.0) use environment. Thus, if the first use environment is the stomach and the second use environment is the small intestine, the quoted language is understood as meaning the natural transfer of a composition comprising drug and polymer from the stomach to the small intestine. If the first and second use environments are in vitro aqueous fluids, the above quoted language is understood as meaning an aqueous test medium (e.g., such as deionized distilled water) having a pH of 1.0 to 2.0 into which drug and polymer are added, the pH of the said medium then being raised, usually slowly, to the range of 5.0 to 7.0.
xe2x80x9cCo-administrationxe2x80x9d as used herein means that a basic drug can be administered separately from, but within the same general time frame as, polymer. Thus a basic drug can, for example, be administered in its own dosage form which is taken at the same time as the polymer which is in a separate dosage form. If administered separately, it is generally preferred to administer both the basic drug and polymer within 15 minutes of each other, in any order, so that both enter the small intestine at or about the same time. For separate administration, it is most preferred that the basic drug and polymer be administered at essentially the same time.
The basic drug and polymer can also be administered after having been admixed together as a dry composition, for example as part of the same dosage form, and administration as a composition is preferred. The composition can be a simple physical combination, homogeneous or non-homogeneous. Homogeneous compositions are preferred and will often, of necessity, result from the manufacturing process itself, for example where multiple dosage units are to be manufactured from a single production batch and homogeneity must accordingly be ensured. Drug and polymer can be physically admixed, as by stirring the dry components together for formulation, together with other components and excipients as known in the art. The drug and polymer may also be physically admixed by granulating as known in the art, with or without other excipients, utilizing, dry granulation, for example tablet slugging or roller compaction, or by wet granulation, as known in the art.
Whether in the form of a physical mixture or a granulated mixture, a dry composition can be used, together with other components and excipients as known in the art, to manufacture tablets, capsules, powders for oral suspension, and unit dose packets by methods well known to the art. Methods of preparing various oral pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18th Edition (1990).
Examples of basic drugs which are advantageously formulated with a polymer according to this invention include:
4-amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)perhydro-1,4-diazepin-1-yl]quinoline
2-[7-(4-Bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
4-(1-Ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;
4-[3-{4-(2-methylimidazol-1-yl)phenylthio}]phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide;
[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;
sertraline; and
ziprasidone
Examples of zwitterionic drugs which are advantageously formulated with a polymer according to this invention are:
(4-{2-[2-Hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethylamino]-propyl}-phenoxy)-acetic acid; and
7-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid.
A composition of matter according to the invention is within the scope of the invention if, when the composition is tested in vivo, the Cmax achieved with said composition is at least 1.25-fold, preferably at least 1.5-fold, more preferably at least 2-fold the Cmax achieved with a control composition (as disclosed below) comprising an equivalent quantity of a basic or zwitterionic drug or salt of either, e.g., a composition lacking polymer. Cmax is well understood in the art as an abbreviation for the maximum drug concentration in serum or plasma of the test subject. In vivo testing protocols can be designed in a number of ways. By measuring the Cmax for a population to which the test composition has been administered and comparing it with the Cmax for the same population to which the control has also been administered, the test composition can be evaluated.
Compositions according to the invention also include those which exhibit at least a 1.25-fold, preferably at least a 1.5-fold, more preferably at least a 2-fold improvement in AUC over a control not containing polymer. AUC is a determination of the area under the curve (AUC) plotting the serum or plasma concentration of drug along the ordinate (Y-axis) against time along the abscissa (X-axis). Generally, the values for AUC represent a number of values taken from all the subjects in a patient test population and are, therefore, mean values averaged over the entire test population. By measuring the AUC for a population to which the test composition has been administered and comparing it with the AUC for the same population to which the control has been administered, the test composition can be evaluated. Alternatively, the AUC test/AUC control ratio may be determined for each subject, them averaged. AUC""s are well understood, frequently used tools in the pharmaceutical arts and have been extensively described, for example in xe2x80x9cPharmacokinetics Processes and Mathematicsxe2x80x9d, Peter E. Welling, ACS Monograph 185; 1986.
Thus, a composition is within the scope of the invention if it effects in vivo either a Cmax or an AUC that is at least 1.25 times, preferably at least 1.5 times, more preferably at least 2.0 times the corresponding Cmax or AUC exhibited by a control composition comprising: an equivalent quantity of drug and excipients, but without polymer. In a preferred embodiment, compositions according to the invention, in addition to displaying at least a 1.25-fold improvement in Cmax as discussed above, also exhibit at least a 1.25-fold improvement in AUC.
Preferred compositions are those which effect a coefficient of variation of Cmax or AUC which is at least 10% less than the coefficient of variation of Cmax and/or AUC observed for a control composition comprising an equivalent quantity of drug and excipients, but without polymer. xe2x80x9cCoefficient of variationxe2x80x9d as used here has its standard meaning, i.e., the ratio of the standard deviation to the mean value for Cmax or AUC. Especially preferred compositions exhibit a coeffient of variation for both Cmax and for AUC which is at least 10% less than the corresponding coefficients of variation for Cmax and AUC observed for said control composition.
Cmax and AUC can be determined in humans or a suitable animal model, such as dogs. If a composition comprising a basic or zwitterionic drug, or a salt of either, admixed with polymer, increases Cmax or AUC by 25% in any species, it is within the scope of the invention.
A drug can be tested in vitro to determine if it exhibits an equilibrium solubility in a pH 1.0 to 2.0 use environment that is at least 3-fold its equilibrium solubility in a pH 5.0 to 7.0 environment. A test drug is dissolved in a pH 1-2 environment, typically aqueous deionized distilled water adjusted to a target pH within the aforesaid pH 1-2 range by adding an appropriate amount of hydrochloric acid. The amount of drug added is an amount sufficient to saturate the aqueous test medium. The test medium can be agitated, typically gently, by means of a stirring bar, overhead stirrer, or the like. Typically the test medium is left to sit (while being agitated) for several hours, typically overnight. The sample can then be filtered or centrifuged as previously described, and solubility in the filtrate or supernate can then be measured by determining the concentration with any suitable means of detection appropriate to the drug. Likewise, the solubility is also determined at pH 5 to 7. If the drug""s pH 1-2 solubility is 3- or more-fold its pH 5-7 solubility, then the drug will benefit from this invention.
A composition can also be tested in vitro to determine whether it is within the scope of the invention. A typical test can be described as follows for a planned dosage form. A quantity of basic drug, zwitterionic drug, or salt of either, usually on the order of 1-5 mg, is dissolved in, as the test medium, an aqueous use environment having a pH of 1.0-2.0, usually 5-40 mL. Generally a single pH within the range, for example a pH of 1.2, is chosen for consistency in results and to facilitate comparison. The drug composition may or may not dissolve completely. The aqueous environment is, as disclosed above, typically deionized, distilled water with sufficient aqueous hydrochloric acid added to adjust the pH to 1.0-2.0. Acid having a normality of 1 to 4 is usually sufficient for adjusting the pH to within 1.0 to 2.0, although a higher concentration can be used if desired. Sufficient acid is present in the test medium such that at least a portion of the drug dissolves while still maintaining the pH of the test medium within a range of 1.0-2.0. It is desirable to agitate the test medium, as by using a stirring bar or an overhead stirrer, and the medium is allowed to stir up to several hours or longer, if desired. An identical drug-containing control sample should be made in the same manner or, alternatively, the drug containing sample test medium already made can, before the addition of any polymer, be split into two equal portions, one being reserved as the control, the other as the test sample. At this point a quantity of test polymer should be added to the test sample in proportion to its intended presence in the final composition. Polymer is omitted from the control sample, although other (non-polymer) excipients can be added.
Control and test can then be adjusted up, as by slow titration, to a standard pH between 5.0 and 7.0, a standard target pH usually being chosen, for example pH 6.5. Titration with aqueous base (or other method of pH adjustment) should be effected over a timespan slow enough, and with a concentration of base dilute enough, so that local precipitation of the drug from solution is minimized, and also to roughly mimic the physiology of gastric emptying into the small intestine. Usually titration using 0.1 to 1 N sodium (or potassium) hydroxide for coarse or rapid pH adjustment in conjunction with 0.01 to 0.1 N sodium (or potassium) hydroxide for fine pH adjustment is effected over a timespan of at least 5 minutes, more preferably over 10 or even 15 minutes. The sample and control can then be filtered (or centrifuged) and the filtrate (or supernate) analyzed by any convenient technique suitable to the drug being tested, such as HPLC, GC, and so forth, using appropriate detection. If the concentration detected at pH 5.0 to 7.0 in the presence of polymer is at least 1.5 times the concentration of that in the control at any time during the 2 hours following titration to pH 5 to 7, the composition or dosage form is within the scope of the invention.
The above test can also be conducted for a pre-formed or pre-manufactured dosage (e.g., a tablet or capsule) already containing polymer. The test is as described above, with a few modifications. First, it may be necessary to pulverize the dosage form if it is a tablet. If the dosage form is a capsule or a powder for oral suspension, then the capsule fill or powder may be tested directly. Since a pre-formed test sample contains test polymer, it will not be possible to split the initial sample into a test portion and control portion. It may accordingly be necessary to make a like composition less the polymer to function as a control. Alternatively, if none of the excipients influences solubility, the control can consist of drug alone, i.e., no other excipients. Generally, initial identical aqueous test medium solutions having a pH of 1.0 to 2.0 should be made, or divided as aliquots out of a common stock, and set aside. Identical quantities of test and control compositions can be added to each and then treated in parallel, as described above.
Thus a composition which is within the scope of this test is one which comprises a basic drug, a zwitterionic drug, or a salt of either, admixed with a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP).
wherein, when said composition is dissolved in an aqueous in vitro test medium having a pH of 1.0 to 2.0, and said test medium is then adjusted to a pH between 5.0 and 7.0, the concentration of said drug in said aqueous pH 5-7 test medium, at any time during the first two hours following said pH adjustment, is at least 1.5-fold the concentration of said drug in a control aqueous test medium containing no polymer.
Compositions within the above in vitro test are provided as a further aspect of the invention.
Compositions are within the scope of the invention if they pass either the in vitro or the in vivo test.
Synthesis of HPMCAS can be conducted by treating O-(hydroxypropyl)-O-methylcellulose with acetic anhydride and succinic anhydride, as set forth in Tezuka et al, Carbohydrate Research 222(1991)255-259 and in Onda et al, U.S. Pat. No. 4,385,078, the teachings of which are incorporated herein by reference. Although such derivatives of cellulose are often considered in the literature as simply having varying average amounts of the four substituents attached to the three hydroxyl groups on each of the glucose repeat units of cellulose, 13C-NMR research suggests that most of the hydroxyl groups initially present on the 2-hydroxypropyl groups are substituted by methyl, acetyl, succinyl, or a second 2-hydroxypropyl group, see U.S. Pat. No. 4,385,078. Although essentially any degree of substitution of the various groups can be used as long as the resulting polymer is soluble at the pH of the small intestine, e.g., pH 5 to 7, the amounts of the substituents methoxy, hydroxypropoxy, acetyl, and succinyl, are generally in the range of 10 to 35 wt %, 3 to 15 wt %, 3 to 20 wt %, and 2 to 30 wt %, respectively. Preferably, the amounts of the substituents are 15 to 30 wt %, 4 to 11 wt %, 4 to 15 wt %, and 3 to 20 wt %, respectively.
Alternatively, HPMCAS, and all of the other aforementioned polymers, may easily be purchased in a number of grades from a number of commercial suppliers such as Eastman Chemical: Co., Kingsport, Tenn.; and Shin Etsu, Tokyo, Japan. For example, HPMCAS is available from Shin Etsu in at least six different grades (LF, MF, HF, LG, MG, HG).
The amount of polymer incorporated into a composition according to the invention is from 1 mg to 10 g per dose for an adult human, preferably 10 mg to 2 g, more preferably 20 mg to 1 g. It is desirable to achieve as high a concentration of polymer in the small intestine as possible, within the practical limits of size for an oral dosage form. For example, if one assumes an availability of approximately 100 mL of fluid in the small intestine, then 200 mg of polymer will form a 2 mg/mL solution. The in vitro test may be used to approximate an appropriate amount of polymer to inhibit precipitation of a particular drug.
Although the key ingredients present in compositions of the present invention can be simply the basic drug to be delivered and polymer, the inclusion of other excipients in the composition may be useful and even preferred. For example, excipients which aid in dosage form disintegration or drug wetting and dissolution or efficient formulation flow or efficient tabletting may be included.
Another type of excipient useful as a component of the compositions herein is a surface-active agent such as a fatty acid and alkyl sulfonate; commercial surfactants such as those sold under tradenames such as benzethanium chloride (Hyamine(copyright) 1622, available from Lonza, Inc., Fairlawn, N.J.), docusate sodium (available from Mallinckrodt Spec. Chem., St. Louis, Mo.), polyoxyethylene sorbitan fatty acid esters (Tween(copyright), available from ICI Americas Inc, Wilmington, Del.), Liposorb(copyright) P-20 (available from Lipochem Inc, Patterson, N.J.), Capmul(copyright) POE-0 (available from Abitec Corp., Janesville, Wis.), and natural surfactants such as sodium taurocholic acid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and other phospholipids and mono- and diglycerides. Such materials can be employed advantageously to increase the rate of dissolution by facilitating wetting, thereby increasing the maximum drug concentration and the degree of supersaturation attained, and also to inhibit crystallization or precipitation of drug by interacting with dissolved drug by mechanisms such as complexation, formation of inclusion complexes, formation of micelles or adsorbing to the surface of solid drug, crystalline or amorphous. These surface active agents may typically comprise up to 25% of the composition.
In addition to mixtures of drug and polymer (and other excipients as discussed immediately above), other conventional formulation excipients can be employed in the compositions of this invention, including those excipients well known in the art. Generally, excipients such as fillers, disintegrating agents, pigments, binders, lubricants, flavorants, and so forth can be used for customary purposes and in typical amounts without affecting the properties of the compositions. These excipients may be mixed or granulated with drug and polymer, or may be added after drug and polymer are mixed or granulated, in order to formulate the composition into tablets, capsules, suspensions, powders for suspension, and the like.
Compositions can also be tested in vivo in dogs as follows:
Beagle dogs (typically n=4-6) that have been fasted the previous day are administered the test or control composition in the fasted or fed state (fasted state: no food is allowed until after an 8 hr blood sample; fed state: a meal of 14 g of dry dog food and 8 g of olive oil (this meal imitates the high fat xe2x80x9cFDA breakfastxe2x80x9d) immediately before dosing test or control composition, and regular rations after the 8 hr sample).
The test and control compositions are administered, via oral gavage in water or 0.2% aqueous polysorbate 80 to aid in wetting, through PE205 tubing attached to a syringe. Dogs are returned to metabolism cages with normal access to water. Alternatively, dosing may be via capsules or tablets. Test and control formulations can be identical except for the presence or absence of polymer. Alternatively, the control formulation can consist of drug alone.
Blood samples are taken from the jugular vein using a 10 ml disposable syringe with a 20 gauge needle at 0.5, 1, 1.5, 2, 3, 4, 6, 8 (and occasionally 12 hr) hours post dose. Other sampling times may be used with the conditions that Tmax is bracketed by the sampling intervals and that an accurate AUC may be calculated. Samples are immediately transferred to clean glass culture tubes containing heparin. Samples are centrifuged at room temperature at 3000 rpms for 5 minutes. Plasma is transferred to clean glass 1 dram vials using a 5 xc2xcxe2x80x3 (13 cm) Pasteur pipette. Plasma samples are frozen on dry ice and stored in a laboratory freezer until assayed by HPLC.
From plasma or serum drug concentrations, typical pharmacokinetic parameters, such as Cmax, Tmax and AUC are calculated for each dog, and then averaged for the test population.
Test compositions or controls can be tested in vivo in humans as follows. In a crossover design, 4 or more healthy human subjects are dosed with a suspension of crystalline drug (or amorphous drug if the drug does not crystallize) or a suspension of the drug/polymer composition. Blood samples are taken before dosing and at a variety of times post-dosing, with the number and temporal distribution of sampling times chosen to bracket Tmax and permit accurate measurement of AUC. Drug concentration in plasma or serum is measured by an appropriate assay, and Cmax, Tmax, and AUC are determined. A composition of this invention is a composition comprising a basic drug, a zwitterionic drug, or a salt of either, admixed with polymer, as previously discussed, which, when tested in vivo:
(a) exhibits a drug Cmax which is greater than 1.25-fold the Cmax determined after dosing said drug, zwitterion, or salt in a control composition not containing polymer; or
(b) exhibits a drug AUC which is greater than 1.25-fold the AUC determined after dosing said drug, zwitterion, or salt in a control composition not containing polymer.
Preferred drug/polymer compositions are those which satisfy both the (a) and (b) criteria above.
Compositions of this invention can be used in a wide variety of forms for administration of drugs orally, usually together with a pharmaceutically acceptable diluent or carrier. Exemplary dosage forms are powders or granules that can be taken orally either dry or reconstituted by addition of water to form a paste, slurry, suspension or solution; tablets, capsules, or pills. Various additives can be mixed, or granulated with the compositions of this invention to form a material suitable for the above dosage forms. Potentially beneficial additives fall generally into the following classes: other matrix materials or diluents, surface active agents, drug complexing agents or solubilizers, fillers, disintegrants, binders, lubricants, and pH modifiers (e.g., acids, bases, or buffers).
Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
Examples of surface active agents include sodium lauryl sulfate and polysorbate 80.
Examples of drug complexing agents or solubilizers include the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins.
Examples of disintegrants include sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, and croscarmellose sodium.
Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth.
Examples of lubricants include magnesium stearate and calcium stearate.
Examples of pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; and buffers generally comprising mixtures of acids and the salts of said acids.
In addition to the above additives or excipients, use of any conventional materials and procedures for formulation and preparation of oral dosage forms using the compositions of this invention known by those skilled in the art can be useful.
The exact dose of composition administered will, of course, differ depending on the specific basic drug of interest, on the subject being treated, on the severity of the condition being treated, on the route of administration and on the judgment of the prescribing physician.
As previously mentioned, for oral administration a pharmaceutical composition suitable for use in this invention can take various forms, including solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets may contain various excipients such as the matrix materials, fillers, diluents, surface active agents, drug complexing agents, solubilizers, disintegrants, binders, lubricants, and pH modifiers exemplified above. Hard gelatin capsule formulations generally comprise drug, polymer, and excipients as described above for tablets. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.